Amino lipid and preparation method and application thereof
An amino lipid and its preparation method as well as an application thereof is provided, and also provided are ionizable amino lipids with a general formula as shown in Formula (I), or pharmaceutically acceptable salts thereof. The amino lipids are used for delivering nucleic acids and small-molecule drugs. The amino lipid compounds have two ester bonds, which enhance the lysosome escape capability of the ionizable amino lipids, and are favorable for the release of delivery targets of a targeted drug or gene, etc., thus improving the delivery efficiency, and showing the capability of delivering nucleic acids into cells in the in-vitro and in-vivo delivery studies.
1 . An amino lipid with the structure as shown in Formula (I):
R 1 is independently selected from E6 and E7,
R 2 is C71,
wherein R 3 , R 4 and L form a carboxylic acid structure of
and
is one selected from:
wherein R 3 is methyl, R 4 is methyl and L is propane-1,3-diyl or pentane-1,5-diyl.
2 . The amino lipid according to claim 1 , being one selected from compounds of the following structures:
3 . A method of preparing the amino lipid according to claim 1 , comprising the following steps:
S1: performing a solvent-free reaction between the compound R 2 COOH and an epoxide compound in the presence of FeCl 3 and Py as catalysts, resulting in a reaction system, wherein the structure of the epoxide compound is described as follows:
and
S2: adding R 3 R 4 NLCOOH to the reaction system obtained from step S1, and allowing the mixture to react in the presence of a condensation agent to obtain the amino lipid;
wherein R 1 , R 2 , R 3 , R 4 , and L are the same as those in claim 1 .
4 . A composition for a nucleic acid administration system, wherein the composition comprises the amino lipid according to claim 1 as a raw material.
5 . A composition formed by the amino lipid according to claim 1 and other lipids, wherein the composition and a nucleic acid drug form a drug preparation, and the nucleic acid drug comprises DNA and RNA.
6 . The composition according to claim 5 , wherein the composition comprises 30 mol %-50 mol % of an amino lipid, 40 mol %-52% mol % of a structure lipid, 5 mol %-20% mol % of an auxiliary lipid and 0.5 mol %-5% mol % of a PEG lipid, wherein the total molar content of the four above ingredients is 100 mol %; and wherein the mass ratio of the amino lipid to the nucleic acid in the composition is in the range of 1:1-50:1.
7 . The composition according to claim 6 , wherein the structure lipid comprises cholesterol and a cholesterol derivative thereof.
8 . The composition according to claim 6 , wherein the auxiliary lipid comprises DSPC, DSPE, DOPE, DOPC and DOPS.
9 . The composition according to claim 6 , wherein the PEG lipid comprises PEG-DMG and PEG-DSPE.
10 . The composition according to claim 6 , wherein the composition is administered by aerosolization administration, intravenous injection, subcutaneous injection, intramuscular injection, ophthalmic administration.